Candida albicans is a fungus that is a common member of the human body’s microbiota. In healthy individuals, it resides on the skin and inside the mouth, throat, gut, and genital areas, where it forms part of the normal microbial community. However, under certain conditions, such as a weakened immune system or disturbances in the normal flora, Candida albicans can overgrow, damage mucosal epithelia, and cause infections. These infections can range from mild, like oral thrush and yeast infections, to severe, life-threatening conditions such as bloodstream infections.

Previous studies have shown that the damage of epithelial cells during Candida albicans infection is almost entirely linked to the secretion of a peptide toxin called candidalysin. Candidalysin shares similarities with pore-forming toxins (PFTs), which insert into their target membranes to form transmembrane pores, causing membrane permeabilization. However, in contrast to all known PFTs, the precursor of candidalysin is located within a complex polyprotein called Ece1, comprising a signal peptide, candidalysin’s precursor (P3), and seven non-candidalysin Ece1 peptides (NCEPs). And while studies have shown that candidalysin is critical for driving C. albicans infections, the roles of NCEPs remained unknown until now.

A recent study unveiled that NCEPs, rather than blocking premature toxin activity, are essential for proper Ece1 folding and candidalysin secretion. The researchers demonstrated NCEPs’ crucial function in preventing candidalysin’s auto-aggregation, ensuring its efficient secretion to the extracellular space.

Through a combination of genetic engineering, mass spectrometry, and anti-candidalysin nanobodies, the researchers dissected the function of each NCEP, showing that alterations trigger an unfolded protein response (UPR), lead to a dysfunctional secretory pathway, and reduce pathogenicity.

Orbit 16 and TethaPod experiments, which evaluated the membrane permeabilization effects of candidalysin in the presence of NCEPs, revealed their role in modulating candidalysin’s activity post-secretion. NCEPs significantly mitigated membrane damage caused by candidalysin, revealing a mechanism by which C. albicans navigates toxin secretion and host interaction.

In conclusion, the study finds out how Candida albicans cleverly packages and delivers its toxin to harm host cells while ensuring its own safety and effectiveness. Understanding this process could help develop new approaches to fight against fungal infections by targeting the toxin’s secretion pathway.

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For more details, please refer to the paper here: Secretion of the fungal toxin candidalysin is dependent on conserved precursor peptide sequences

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